title: A 3D linear solvation energy model to quantify the affinity of flavonoid derivatives toward P-glycoprotein.
abstract: P-glycoprotein (Pgp/ABCB1) both accounts for multidrug resistance (MDR) in chemotherapy and contributes to reduce oral bioavailability and brain distribution of drugs. Flavonoids, reported as potent Pgp inhibitors, are able to bind to the cytosolic ATP-binding site and a vicinal hydrophobic pocket. In order to explore the interaction forces governing the affinity of flavonoids towards Pgp, the 3D quantitative structure-activity relationship (QSAR) approach was used to analyze a set of flavonoid derivatives. The variation of affinity towards Pgp was investigated by VolSurf descriptors of Molecular Interaction Fields (MIFs) related to hydrophobic interaction forces, polarizability, and hydrogen-bonding capacity. The 3D linear solvation energy VolSurf model developed here identifies shape parameters and hydrophobicity as the major physicochemical parameters responsible for the affinity of flavonoid derivatives towards Pgp and hydrogen-bonding capacities as minor modulators of this activity. Furthermore, this predictive model (q(2) of 0.71) was also validated by use of an external set of 10 flavones.
authors.affiliation: Unité de pharmacochimie, School of Pharmaceutical Sciences, Université de Genève, Université de Lausanne, Quai Ernest-Ansermet 30, CH-1211 Genève 4, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Boccard
authors.forename: Fania
authors.initials: F
authors.lastname: Bajot
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
authors.forename: Serge
authors.initials: S
authors.lastname: Rudaz
authors.forename: Ahcène
authors.initials: A
authors.lastname: Boumendjel
authors.forename: Edwige
authors.initials: E
authors.lastname: Nicolle
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000378:metabolism; D001572:Benzofurans / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D047188:Chalcones / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D005419:Flavonoids / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D016018:Least-Squares Analysis; D008958:Models, Molecular; D015394:Molecular Structure; D025341:Principal Component Analysis; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D044004:Xanthones / Q000737:chemistry / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001572:Benzofurans; D047188:Chalcones; D005419:Flavonoids; D044004:Xanthones